An Oncogenic Role for the Ubiquitin Ligase UBE2O by Targeting AMPK-α2 for Degradation

Hardie, D. Grahame

doi:10.1016/j.ccell.2017.01.010

Cited by 6 publications

(4 citation statements)

References 10 publications

(10 reference statements)

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“…Numerous studies demonstrate that AMPK activities are primarily regulated via T172 phosphorylation by the upstream kinase LKB1 or CaMKK2 (5,14,32). AMPKα protein stability can be modulated by ubiquitin ligase UBE2O or MAGE-A3/6-TRIM28 (7,33). In this study, we demonstrate that transcription of AMPKα1 is suppressed in response to activation of PI3K/HER2, leading to disruption of cell-cell adhesion and promoting cancer metastasis.…”

Section: Discussionmentioning

confidence: 53%

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation

Chen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell–cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell–cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell–cell adhesion and cancer metastasis.

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Section: Discussionmentioning

confidence: 53%

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation

Chen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…These opposing roles for AMPK in cancer may depend on several factors, including cell type, context, and the expressed AMPK isoform. Emerging evidence suggests that the AMPKα2 subunit is a tumor suppressor, but the more commonly expressed AMPKα1 isoform is an oncoprotein [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK

et al. 2021

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PHLPP2 is a member of the PHLPP family of phosphatases, known to suppress cell growth by inhibiting proliferation or promoting apoptosis. Oncogenic kinases Akt, S6K, and PKC, and pro-apoptotic kinase Mst1, have been recognized as functional targets of the PHLPP family. However, we observed that, in T-leukemia cells subjected to metabolic stress from glucose limitation, PHLPP2 specifically targets the energy-sensing AMP-activated protein kinase, pAMPK, rather than Akt or S6K. PHLPP2 dephosphorylates pAMPK in several other human cancer cells as well. PHLPP2 and pAMPK interact with each other, and the pleckstrin homology (PH) domain on PHLPP2 is required for their interaction, for dephosphorylating and inactivating AMPK, and for the apoptotic response of the leukemia cells to glucose limitation. Silencing PHLPP2 protein expression prolongs the survival of leukemia cells subjected to severe glucose limitation by promoting a switch to AMPK-mediated fatty acid oxidation for energy generation. Thus, this study reveals a novel role for PHLPP2 in suppressing a survival response mediated through AMPK signaling. Given the multiple ways in which PHLPP phosphatases act to oppose survival signaling in cancers and the pivotal role played by AMPK in redox homeostasis via glucose and fatty acid metabolism, the revelation that AMPK is a target of PHLPP2 could lead to better therapeutics directed both at cancer and at metabolic diseases.

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“…In addition, activated AKT can directly phosphorylate AMPKα on Serine 485, resulting in AMPK conformational changes and blockage of AMPKα T172 from phosphorylation103, 104. Recent studies demonstrated that ubiquitin ligases UBE2O or MAGE-A3/6-TRIM28 can promote ubiquitination of AMPKα, resulting in proteasome- dependent degradation and an increase in cell proliferation and tumor growth105, 106. Furthermore, knockout of AMPKα can enhance c-Myc-induced lymphoma progression107.…”

Section: Metformin Ampk and P53 Family Proteinsmentioning

confidence: 99%

Role of p53 Family Proteins in Metformin Anti-Cancer Activities

Yi¹,

Zhang²,

Yi³

et al. 2019

J. Cancer

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Metformin has been used as therapy for type 2 diabetes for many years. Clinical and basic evidence as indicated that metformin has anti-cancer activities. It has been well-established that metformin activates AMP-activated protein kinase (AMPK), which in turn regulates energy homeostasis. However, the mechanistic aspects of metformin anti-cancer activity remain elusive. p53 family proteins, including p53, p63 and p73, have diverse biological functions, including regulation of cell growth, survival, development, senescence and aging. In this review, we highlight the evidence and mechanisms by which metformin inhibits cancer cell survival and tumor growth. We also aimed to discuss the role of p53 family proteins in metformin-mediated suppression of cancer growth and survival.

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An Oncogenic Role for the Ubiquitin Ligase UBE2O by Targeting AMPK-α2 for Degradation

Cited by 6 publications

References 10 publications

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation

Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK

Role of p53 Family Proteins in Metformin Anti-Cancer Activities

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